Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial

Abstract

Background: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge.

Methods: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21).

Results: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum β-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator.

Conclusions: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated.

Clinical trial registration: NCT03357614.

Keywords: acute pyelonephritis; complicated urinary tract infection; sulopenem.

Conflict of interest statement

Potential conflicts of interest. M. W. D., S. I. A., S. P., K. A., and M. T. Z. report being employees of Iterum Therapeutics during the conduct of the study and owning stock in Iterum Therapeutics. A. F. D., M. W. D., and J. B. report receiving consulting fees from Iterum Therapeutics. S. I. A. is a board member of the Connecticut Infectious Disease Society. A.F.D. reports consulting fees for ContraFect, UTILITY, MicuRX, and Paratek and participates on a data and safety monitoring board for Paratek. M. W. D. reports patents pending for Iterum Therapeutics and is on the Iterum Therapeutics Board of Directors. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Analysis population disposition. Abbreviations: CFU, colony-forming unit; ITT, intent-to-treat; MITT, modified intent-to-treat; mMITT, microbiologic modified intent-to-treat.

Figure 2.

Time to resolution (days) of all cUTI symptoms, survival and without nonstudy antibiotic use. Patients who received rescue antibiotic prior to resolution or who died without resolution were censored at day 29. Abbreviation: cUTI, complicated urinary tract infection.

Figure 3.

Distribution of sulopenem minimum inhibitory concentrations in the sulopenem treatment group.

Figure 4.

Distribution of ciprofloxacin minimum inhibitory concentrations in ertapenem patients with ciprofloxacin-susceptible organisms at baseline.